1-aminoalkyl-dibenzosemi-bullualenes and the salts thereof

ABSTRACT

1-Aminoalkyl-dibenzosemibullvalenes, e.g., those of the formula   Am an amino group ALK ALKYLENE R1,2 H, alkyl, free, etherified or esterified o0h or SH, CF3, NO2, amino or acyl ACYL DERIVATIVES, N-oxides, quaternaries and salts thereof are antidepressants.

United States Patent [191 Huebner [111 3,818,020 [4 June 18, 1974 l-AMINOALKYL-DIBENZOSEML BULLUALENES AND THE SALTS THEREOF [75] Inventor: Charles Ferdinand Huebner,

Chatham, NJ.

[73] Assignee: CiIba-Geigy Corporation, Ardsley,

[22] Filed: Mar. 12, 1971 [21] Appl. N0.: 123,822

[52] US. Cl... 2611/2955 S, 260/239 E, 260/501.l1, 260/239 B, 260/501.l2, 260/239 BA, 260/501.18, 260/243 B, 260/50l.21, 260/247.1, 260/515 R, 260/247.2 B, 260/515 A, 260/518 R, 260/247.5 B, 260/519, 260/247.7 F, 260/544 M, 260/268 FC, 260/556 A, 260/290 R, 260/556 AR, 260/290 l-lL, 260/556 B, 260/293, 260/556 C, 260/293.4 A, 260/558 R, 260/294.3, 260/558 S, 260/294.7, 260/559 R, 260/326.14 T, 260/559 TT, 260/326.3, 260/562 P, 260/326.5 C, 260/562 A, 260/326.8l, 260/567.5, 260/326.84, 260/567.6 M, 260/326.85, 424/280, 424/329, 260/340.2, 424/330, 260/343.7, 260/570.8 TC, 260/456 P, 260/570.9,

260/456 E, 260/648 R, 260/469, 204/162 R, 204/163 YR, 260/471'A, 424/246, 424/248, 260/473 F, 424/250, 424/251, 260/488 CD,

[51] Int. Cl. C07c 87/28 [58] Field of Search 260/570.8 TC, 570.9, 326.14, 260/295.5 S, 501.11, 501.12, 501.21, 343.7

[56] References Cited UNITED STATES PATENTS 1/1970 Ciganek 260/578 X Primary ExaminerRobert V. Hines Attorney, Agent, or Firm-Harry Goldsmith; Mario A. Monaco [57] ABSTRACT 1-Aminoalkyl-dibenzosemibullvalenes, e.g., those of the formula elk-A In 9 atfar rind gr ou alk alkylene R H, alkyl, free, etherified or esterified 00h or SH, CF N0 amino or acyl acyl derivatives, N-oxides, quaternaries and salts thereof are antidepressants.

9 Claims, N0 Drawings l-AMliNOALKYL-DIEENZOSEMI-BULILUALIENES AND 'lili-IE SALTS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new l-aminoalkyl-dibenzo-tricyclo[3.3.O.0 ]octa3,6-dienes (l-aminoalkyldibenzosemibullvalenes), more particularly of those corresponding to Formula I R: alk-Am in which each of Ph and Ph is a 1,2-phenylene radical, alk is lower alkylene, Am is an amino group, R is hydrogen, etherified or esterified hydroxy, an aliphatic, araliphatic or aromatic radical or lower alkylene linked with Am, and each of R and R is hydrogen, free, etherified or esterified hydroxy or an aliphatic radical, of acyl derivatives, N-oxides, quatemaries and salts thereof, as well as of corresponding pharmaceutical compositions and of methods for the preparation and application of these products. Said products are useful antidepressants, for example, in the treatment or management of exoor endogenous depressions.

DESCRIPTION OF THE PREFERRED EMBODIMENT The 1,2-phenylene radicals Ph, and Ph are unsubstituted or substituted in the remaining 4 positions by one or more than one, preferably one or two, of the same or different substituents, for example, lower alkyl, e.g., methyl, ethyl, nor i-propyl or -butyl, free, etherified or esterified hydroxy or mercapto, such as lower alkoxy or alkylmercapto, e.g., methoxy, ethoxy, nor ipropoxy or -butoxy, methylmercapto or ethylmercapto, lower alkanoyl oxy, e.g. acetoxy, halogeno, e.g. fluoro, chloro or bromo, trifluoromethyl, nitro, amino, preferably di-lower alkylamino, e.g., dimethylamino or diethylamino, or acyl, such as lower alkanoyl or lower alkylsulfonyl, e.g., acetyl, propionyl, pivaloyl, methylor ethylsulfonyl. More particularly the radicals Ph, and Ph represent R -l,2-phenylene, wherein R is hydrogen, lower alkyl, hydroxy lower alkoxy, halogeno, trifluoromethyl, nitro, amino or di-lower alkylamino. The term lower, referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

The lower alkylene radical alk and/or R is preferably methylene, but also l,l-or 1,2-ethylene, l,l-, 1,2-, 2,2- or 1,3-propylene, l,l, 1,2-, 2,2-, 1,3-, 2,3- or 1,4- butylene.

The amino group Am is a primary, preferably a secondary or tertiary amino group, containing advantageously one or two radicals of aliphatic or one of aromatic nature. Such amino groups are, for example, monoor di-lower alkylamino, e.g., methyl amino, ethylamino, i-butylamino, dimethylamino, N-methyl- N-ethyl-amino, diethylamino, di-nor Lpropylamino or di-n-butylarnino; 3 to 7 ring'zmembered cycloalkylamino, cycloalkyl-lower alkyllamino, di-lower alkylamino-lower alkylamino, HPh -lower alkylamino or HPh amino and the tertiary N-lower alkyl derivatives thereof, e.g., cyclopropylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, 2- dimethylamino-ethylamino, benzylamino, 2- phenethylamino or phenylamino and the tert. N- (methyl, ethyl, n-or i-propyl or-butyl)-derivatives thereof, monoor bicyclic lower alkyleneimino or alkenyleneiminio, e.g., ethyleneimino, pyrrolidino, pyrrolino, piperidino, 1,4-pentyleneimino, 2,5- or 1,6- hexylene-imino or 2,6-heptyleneimino; 2-aza-2-bicyclo [2,2,1]heptyl, 2-aza2-bicyclo [2,2,2] or [3,2,1]octyl, 3-aza-3'bicyclo [3,2,1] or [3,3,0]octyl, 2-aza-2- bicyclo[3,2,2] or [3,3,1]nonyl, 3-.aza-3-bicyclo [3,2,2] or [3 ,3,1]nonyl, 2-aza-2-, 3-aza-3, 7-aza-7-or 8- a za; bicy l o[4 ,3,0]nonyl or 2-aza-2- or 3-aza-3 -bicyclo [4,4,0]decyl, or monocyclic inonoaza-, -oxaor -thia-lower alkyleneimino or N-(lower alkyl, hydroxylower alkyl, l-llh -lower alkyl or HPh,)-monoaza-lower alkyleneimino, wherein 2 heteroatoms are separated by at least 2 carbon atoms, e.g., piperazino, 4-(methyl, ethyl, Z-hydroxyethyl, benzyl or phenyl)- piperazino, 3-aza-l,6-hexyleneimino, 3-(methyl or eth' yl )-3-aza-l ,6-hexylene-imino, 4-aza-l ,7 heptyleneimino or 4-(methyl or ethyl)-4-aza-l,7- heptyleneimino, morpholino, 3,5-dimethyl-morpholino or thiamorpholino. The amino group Am may also be linked with a lower alkylene moiety R, thus forming another ring system of which the moiety -alk-Am-R- is connected with the cyclopropane ring and Am is a ringmember of said ring system. It preferably is 5- membered, i.e. each of alk and R are methylene.

An aliphatic radical R, R, and R is, for example, lower alkyl, e.g., that mentioned above, or lower alkenyl, e.g., vinyl or allyl, which radicals may contain functional groups, such as free, etherified or esterified hydroxy, prim., sec. or tert. amino and/or oxo, e.g., (hydroxy, lower alkoxy, halogeno, Am and/or oxo)-lower alkyl, such as (hydroxy, methoxy, ethoxy, chloro or dimethylamino)-methyl, formyl, carboxy or carbolower alkoxy, 1- or 2-(hydroxy, methoxy, ethoxy, chloro, dimethylamino, carboxy or carbomethoxy)- ethyl or -propyl, lower alkanoyl, e. g., acetyl or pivaloyl.

An araliphatic or aromatic radical R is, for example, l-lPh -lower alkyl, -alkanoyl or -hydroxyalkyl or l-IPh respectively, e.g., benzyl, 1- or 2-phenethyl, benzoyl, phenylacetyl or a-hydroxybenzyl; phenyl, tolyl, anisyl, halophenyl, nitrophenyl, aminophenyl or acetylphenyl.

R preferably represents hydrogen, halogeno, lower alkyl, hydroxy-lower alkyl, lower alltoxy-lower alkyl, halogeno-lower alkyl, Am-lower alkyl, carboxyl, carbolower alkoxy, R phenyl-lower allcyl or R -phenyl, in which R, has been defined above. Each of R and R preferably represents hydrogen, lower alkoxy, halogeno, lower alkyl, hydroxy-lower alkyl, halogenolower alkyl, above all trifluoromethyl, carboxy or carbo-lower alkoxy.

Acyl derivatives of primary or secondary amines of Formula I are preferably those of aliphatic or araliphatic carboxylic or sulfonic acids, such as of lower alkanoic, lower alkanesulfonic, R -phenyl-lower alkanoic or R -benzenesulfonic acids, e.g., of acetic, propionic, pivalic, methanesulfonic, ethanesulfonic, benzoic, phenylacetic or p-toluenesulfonic acid.

Quaternaries and salts of the compounds of Formula I are preferably lower alkyl or R -phenyl-lower alkyl quaternaries and acid addition salts.

The compounds of the invention exhibit valuable pharmacological properties, for example, imipraminetype antidepressant andamphetamine potentiating effects. This can be demonstrated in animal tests, using advantageously mammals, such as mice, rats or monkeys, as test objects. The compounds of the invention can be applied to the animals enterally, e.g., orally, or parenterally, e.g., subcutaneously or intraperitoneally, preferably in the form of capsules or aqueous solutions or suspensions. The dosage may range between about 0.1 and 75 mg/kg/day, preferably between about 1 and 50 mg/kg/day, advantageously between about and 25 mg/kg/day, whereby the enterally administered dosage form is preferred. The antidepressant activity is being observed, for example, in mice by antagonizing either the ptosis induced by tetrabenazine or the hypothermia caused by reserpine, or in rats by potentiation of amphetamine. The latter test is performed according to P. Carlton, Psychopharmacologia 1961, Vol. II, p. 364, with about 8 month old male rats, which are trained to press a bar every 30 seconds, in order to avoid an electric shock applied through the floor grid. In case the animals receive 0.25 mg/kg/day of amphetamine, their performing rate for avoiding said shocks during a test period of about 2% hours is higher than that of placebo (saline) treated animals. In case the animals receive the compounds of the invention in the above-mentioned doses and about 45 minutes later the amphetamine, their rate of avoidance is highest, as compared with that of animals receiving a) saline alone, b) saline and amphetamine or c) the compounds of the invention and saline. In monkeys, e.g., squirrel or rhesus monkeys, antidepressant activity can be observed without sedation. For example, according to an avoidance schedule the monkey must press a lever within a certain time interval to avoid the onset of an electric foot shock. Each lever press postpones the shock for 20 seconds and if the monkey fails to press the lever, 0.5 second shocks are delivered at 20 second intervals, unless the animal again presses the lever. Another schedule required the animal to press the lever times within seconds in the presence of a neutral stimulus, i.e., a steady white light over the lever, to obtain a food reinforcement. The compounds of the invention produce in this test an increase in performance, which is maintained for several, e.g., 4 hours. Accordingly, the compounds of the invention are useful antidepressants in the treatment or management of exoor endogenous depressions, but also useful intermediates in the preparation of other valuable products, especially of pharmacologically active compounds.

Particularly useful are the compounds of Formula I, in which each of Ph, and Ph is R -l,2-phenylene, alk is lower alkyl-ene, Am is amino, monoor di-lower alkylamino, 3 to 7 ring-membered cycloalkylamino or 4 cycloalkyl-lower alkylamino, lower alkyleneimino, monoaza-, oxaor thia-lower alkyleneimino or N- (lower alkyl or hydroxy-lower alkyl)-monoaza-lower alkyleneimino wherein 2 hetero atoms are separated by at least 2 carbon atoms, R is hydrogen, lower alkyl, hydroxy-Iower alkyl or R -phenyl, each of R, and R is hydrogen or lower alkyl and R is hydrogen, lower alkyl, lower alkoxy, halogeno, trifluoromethyl, nitro, amino or di-lower alkylamino, the N-oxide, lower alkyl quatemaries or acid addition salts thereof.

Preferred compounds of the invention are those of Eeqnplainm r .7 .7

R5 B5 (II) in which Am, is amino, monoor di-Iower alkylamino, '3 to 5 ring-membered cycloalkylmethylamino, 5 to 7 ring-membered lower alkylene-imino, piperazino, morpholino, thiamorpholino or N-(lower alkyl, 2- or 3- hydroxy-lower alkyl)-piperazino, R is hydrogen, methyl, hydroxymethyl or phenyl, each of R and R is hydrogen or methyl, each of R and R is hydrogen, methyl, methoxy, chloro or nitro and n is the integer 1, 2 or 3, the N-oxide or a therapeutically acceptable acid addition salt thereof.

Especially valuable are the compounds of Formula II, in which Am, is amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylmethylamino, pyrrolidino, piperidino, piperazino, 4-methylpiperazino or 4-(2-hydroxyethyl)-piperazino, R is hydrogen, hydroxymethyl or phenyl, each of R and R is hydrogen, each of R and R is hydrogen, methyl or chloro and n is the integer l, 2 or 3, the N-oxide of a therapeutically acceptable acid addition salt thereof.

Outstanding are the compounds of Formula III in which Am is amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylmethylamino, pyrrolidino, piperidino, piperazino, 4-methylpiperazino or 4-(2-hydroxyethyl)-piperazino, R is hydrogen,

methyl or chloro and n is the integer l, 2 or 3, the N- cording to methods known per se. For example, they (III) are obtained by converting in a compound of the formula in which X is a substituent capable of being converted into alk-Am, X into said aminoalkyl group and, if desired, converting any resulting compound into another compound of the invention.

The substituent X is, for example a reactively esterified hydroxyalkyl group, for example, such derived from a strong mineral acid, particularly a hydrohalic acid, e.g., hydrochloric or hydrobromic acid, a sulfuric or sulfonic acid, such as a lower alkane or benzene sulfonic acid, e.g., methane, ethane or p-toluene sulfonic acid, or a phosphoniumalkyl group, e.g., a triphenyl-phosphoniumalkyl halide group. Said groups are converted into aminoalkyl by condensation with H-Am or an alkali metal, e.g., sodium salt thereof. X may also be a metallic group, preferably an alkali metal atom, e.g., lithium, or halomagnesium, and the corre sponding metal organic compound reacted with a reactively esterified aminoalkanol or an unsubstituted or N-substituted ethyleneimine.

Another substituent X is, for example, a (nitro, ox imino, imino, cyano, carbamoyl, isocyanato or esteritied carboxyamino, e.g., carbalkoxyamino)-alkyl, -alkenyl, -alkanoyl or -hydroxyalkyl group, an aminoalkenyl, -alkan0yl or -hydroxyalkyl group, cyano or preferably carbamoyl, e.g., COAm, which radicals can be converted into aminoalkyl by reduction and/or hydrolysis. Said reduction is carried out under mild and careful conditions, so as to prevent opening of the cyclopropane ring. The above nitro compounds, nitriles, amides, isocyanates, urethanes or alkanoyl compounds are advantageously reduced with the use of simple or complex light metal hydrides, e.g., boron hydride or alkali metal boron or aluminum hydrides, such as lithium aluminum hydride or sodium boron hydride. In this reduction, the cyano and carbamoyl groups are converted into aminomethyl groups, the isocyanato or esterified carboxyamino groups into methylamino groups and the alkanoyl groups into alkyl or whydroxy alkyl groups. Said oximes, Schiffs bases (i.e., iminoalkylor aminohydroxyalkyl compounds) of said w-amino-ahydroxyalkyl reduction products of the alkanoyl compounds, as well as the nitro compounds and aminoalkenyl compounds, are preferably reduced with nascent hydrogen, such as hydrogen generated electrolytically or by the action of metals on acids or alcohols, e.g. zinc or iron and mineral or alkanoic'acids, sodium or aluminum or their amalgams and lower alkanols. Also carefully controlled catalytic reduction may be applied, i.e., hydrogen in the presence of nickel, palladium or platinum catalysts. Isocyanates and urethanes may also be subjected to hydrolysis, e.g., with the use of aqueous mineral acids or alkalis.

The compounds of the invention so obtained can be converted into each other according tomethods known per se. For example, resulting primary, secondary or tertiary amines can be reacted with reactive esters of the corresponding alcohols, with lower alkyleneoxides, e.g., ethyleneoxide, or with aldehydes or ketones and reducing agents, e.g., formic acid or its functional der e or n sss tthydw sw in dette b i 1 99:

d dary or tertiary amines, or qua'ternaries respectively. Resulting primary or secondary amines can also be acylated, for example, with the use of the corresponding acid halides or anhydrides, or acyl derivatives obtained hydrolyzed, e.g., with acids or alkalies, or reduced with simple or complex light metal hydrides. Resulting tertiary amines can be converted into N-oxides or secondary amines, for example by treating them with oxida tion or acylating agents, such as hydrogen peroxide or peracids, or acid halides or anhydrides respectively, e.g., aliphatic or aromatic percarboxylic acids or halo formic acid esters. Furthermore, nitro groups may be introduced into aromatic moieties, e.g., by the action of nitric-sulfuric acid or by pyrolysis of nitrates, advantageously in acidic media, e.g., in trifluoroacetic acid, or nitro groups present therein reduced, e.g., with nascent hydrogen. Resulting hydroxy-compounds, e. g., those of Formula l in which R is hydroxyalkyl, can be esterified and/or etherified, e.g., with the use of acid halides or anhydrides, including thionyl or phosphorus halides or oxyhalides, if desired, followed by the action of lower alkanols or alkali metal alkoxides. Resulting acids can be esterified with the corresponding alcohols in the presence of a strong acid, e.g., hydrochloric, sul furic, benzene or p-toluene sulfonic acid, or with diazo compounds, and resulting esters hydrolyzed or transesterified in the presence of acidic or alkaline agents, e.g., mineral or complex heavy metal acids or alkali metal carbonates or alcoholates. A resulting acid can also be decarboxylated or converted into its salts according to conventional methods, for example, by pyrolysis in the presence or absence of catalysts, e.g., copper powder, or by treatment with an about stoichiometric amount of a suitable saltlorrning reagent, respectively, such as ammonia, an amine or an alkali or alkaline earth metal hydroxide, carbonate or hydrogen carbonate. A salt of this type can be reconverted into the free acid by treatment with an acid, e.g., hydrochloric, sulfuric or acetic acid until the proper pH has been reached. A resulting basic compound can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, such as a therapeutically useful acid, or with. a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with .a base, e.g., a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic acids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, e.g., carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic and cyclohexyl-sulfamic acid; methionine, tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used for purification of the resulting free compounds, which are converted into salts, the salts separated and the free compounds liberated from the salts. in view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixture of isomers can be separated into the single isomers by methods in themselygs known, e.g., by fractional distillation, crystallization and/or chromatography. Racemic products (containing either an asymmetrical carbon atom or no center of symmetry) can likewise be resolved into the optical antipodes, for example by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The above reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing, neutralizing agents and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The invention also comprises any modification of the above process, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salts or reactive derivatives. Those starting materials are preferably used, which lead to those compounds of the invention, which are indicated above as the preferred embodiments of the invention.

The starting material used is known or, if new, may be prepared according to the methods illustrated by the examples or described in J. Am. Chem. Soc. 88, 2882 (1966) and 90, 4465, i.e., by irradiation of corresponding 9,10-ethenoanthracenes with light having a 6 3000 A in the presence or absence of photosensitizers, preferably ketonic sensitizers, e.g., acetone, acetophenone or benzophenone. The semibullvalenes obtained can then be converted into the other starting materials as described for the final products of the invention. For example, resulting esters can be hydrolyzed or transesterified in the presence of acidic or alkaline agents, e.g., mineral or complex heavy metal acids or alkali metal carbonates or alcoholates, or treated with H-Am. Resulting acids can be converted into their halides by treatment with thionyl or oxalyl halides or phosphorushalides or oxyhalides. Resulting acid halides may be treated with alcohols, ammonia or amines and resulting metal or ammonium salts with aliphatic or araliphatic halides or chlorosulfites, thionyl halides, phosphorus oxide, halides or oxyhalides or other acyl halides as well as alkali metal cyanides, in order to obtain the corresponding esters, halides, anhydrides, amides or the nitrile respectively. Resulting amides can be hydrolyzed under acidic or alkaline conditions, e.g., with the use of aqueous mineral and/or carboxylic acids or alkali metal hydroxides, also alcoholized or transaminated. A resulting ester, salt or nitrile, containing in a-position at least one hydrogen atom or a l-halo compound, can be metallized in said aor l-position, e.g., with the use of alkali metals or reactive derivatives thereof, e.g., organic metal compounds, such as phenyl or butyl lithium, triphenylmethyl sodium or sodium amides or alcoholates, and thereupon reacted with ethylene oxide, a reactive ester of a corresponding alcohol or a corresponding functional acid derivative, e.g., an unsubstituted or correspondingly substituted lower alkyl or alkanoyl halide. Starting material in which X contains more than one carbon atom can be obtained from that in which X is halomethyl according to the wittig reaction to yield said phosphonium compounds.

.iv ish Readily available compounds in which X is acetyl, can be converted into corresponding amides according to the Willgerodt-Kindler reaction or may be halogenated and aminated in order to yield the compounds in which X is Am-lower alkanoyl. The latter compounds can also be obtained by aminomethylation according to Mannich, i.e., reaction of the l-lower alkanoyl derivatives with formaldehyde or a derivative thereof, e.g.. paraformaldehyde. and HAm. The l-aminoalkanoyl compounds so obtained can be reduced, for example with sodium boron hydride or a Grignard'compound, to yield l-(u -Am-a-hydroxyalkyl)-compounds. These can be dehydrated, e. g., with sulfuric or phosphoric acid, to yield corresponding aminoalkenyl compounds. Compounds in which X is formyl, can be reacted with nitromethane in order to yield corresponding 2-nitroethenyl compounds. Finally, the isocyanates and urethanes can be obtained from said acid halides and sodium azide, and decomposing the resulting azide according to-Curtius, i.e., by pyrolysis in the presence or absnece of an alcohol, such as a lower alkanol.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also c) binders, e.g., magne-, sium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, enzymes of the binders and/or effervescent mixtures and e) adsorbents, colorants, flavors and/or sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to percent, preferably about 1 to 50 percent of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by EXAMPLE 1 w ric acid, the extract made basic with ammonia and the mixture extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from aqueous ethanol, to yield the ldimethylaminomethyl-clibenzosemibullvalene of the formula melting at 80.

1 g thereof is taken up in the minimum amount of anhydrous ethanol, the solution acidified with ethanolic hydrochloric acid and the precipitate formed recrystallized from ethanol-diethyl ether, to yield the corresponding mono-hydrochloride melting at 252254.

The starting material is prepared as follows: The solution of 10 g l l-carboxy-9,lO-ethenoanthracene in 250 ml tetrahydrofuran is irradiated by a low-pressure ultraviolet lamp until no starting material can be detected by NMR-analysis. It is evaporated and the residue recrystallized from ethanol, to yield the l-carboxydibenzosemibullvalene melting at 230232.

The mixture of g thereof and 30 ml thionyl chloride is allowed to stand for 2 days at room temperature and evaporated in vacuo, to yield the corresponding acid chloride melting at l76l78.

To the solution of g thereof in 50 ml ethyl acetate, 24 ml of a 4.6N dimethylamine solution in ethyl acetate are added while cooling and stirring. The mixture is allowed to stand at room temperature for 2 hours, evaporated in vacuo, and the residue triturated with water, to yield the l-dirnethylcarbamoyldibenzo-semibullvalene melting at 204205.

EXAMPLE 2 To the mixture of 1.4 g l-bromomethyldibenzosemibullvalene and 1 ml benzene, 5m] 5.1N ethanolic dimethylamine are added and the mixture heated in a sealed tube to 100 for 24 hours. It is evaporated, the residue taken up in diethyl ether and the solution extracted with 5 percent hydrochloric acid. The aqueous phase is made basic with ammonia and extracted with diethyl ether. The extract is dried, evaporated, and the residue recrystallized several times from aqueous ethanol, to yield the ldimethylaminomethyldibenzosemibullvalene, which is identical with the product obtained according to Example 1.

The starting material is prepared as follows: The solution of 10 g ll-carbethoxy-9,lO-ethenoanthracene is 200 ml cyclohexane is irradiated for 1 week with a lowpressure ultraviolet lamp, during which time it is filtered several times. It is evaporated in vacuo and the residue recrystallized from ethanol, to yield the 1- carbethoxy-dibenzosemibullvalene melting at 13 l-l36.

The solution of 3 g thereof in the minimum amount of anhydrous diethyl ether is added dropwise to the suspension of 0.76 g lithium aluminum hydride in 15 ml diethyl ether While stirring, and the mixture is refluxed for 6 hours. After standing overnight at room temperature, it is combined with 1 ml ethyl acetate, 0.7 ml water, 1.5 ml 12 percent sodium hydroxide and 2.3 ml water, in this order, and filtered. The filtrate is evaporated in vacuo and the residue recrystallized from ethanol, to yield the l-hydroxymethyl-dibenzosemibullvalene melting at 139- 1 42.

EXAMPLE 3 According to the method described in Example 1, the compound of the formula CgH N C \GHZ k1. R.absorption at 3650, 2755, 1355, 1020, 750

740 and 700 cm is prepared from the corresponding cyclic N-ethylimide and equivalent amounts of lithium aluminum hydride. Said N-ethylimide is obtained either from the 1,2- dicarboxy-dibenzosemibullvalene and aqueous ethylamine, evaporating the solution of the bis-ethylammonium salt and heating the latter in N-ethylpyrrolidone to about -200, or from the dibenzosemibullvalene-l,2-dicarboxylic acid lactone and ethanolic ethylamine at elevated temperature and pressure.

According to the method described in Example 2, the l-pyrrolidinomethyl-dibenzosemibullvalene can be prepared.

By analogous irradiation of a cyclohexane solution of l l-( 2-dimethylaminoethyl)-9, IO-ethenoanthracene containing some acetone as photosensitizer, the l-( 2- dimethylaminoethyl)-dibenzo-semibullvalene is obtained; it may be converted into its hydro-chloride as shown in the previous examples.

The starting material can be prepared as follows: The mixture of 200 g anthracene, 96 g 3-butynol, 2.5 g hydroquinone and 600 ml toluene is heated in an autoclave to about 210 for 15 hours. It is filtered, the residue washed with acetonitrile and the filtrate evaporated in vacuo. The residue is taken up in the minimum amount of methanol at room temperature and the mixture chilled in the refrigerator. It is filtered, the filtrate evaporated in vacuo, the residue taken up in the minimum amount of chloroform-ethyl acetate (9:1 the solution chromatographed on silica and the eluate obtained with ethyl acetate evaporated, to yield the 1 l- (2-hydroxyethyl)-9,lO-etheno-anthracene having an R, of 5.5.

To the solution of 2.8 g thereof in 100 ml diethyl ether, 0.7 ml phosphorus tribromide are added during 10 minutes at 70 while stirring, and stirring is continued at room temperature for 5 hours. The mixture is carefully combined with water, the precipitate formed filtered off and recrystallized from acetone, to yield the 1 l-(2-bromoethyl)-9, l O-etheno-anthracene melting at 180.

The mixture of 5 g thereof 50 ml benzene and 60 ml 5N ethanolic dimethylamine is allowed to stand at room temperature for 1 week. It is evaporated in vacuo, the residue taken up in diethyl ether, the solution extracted with percent hydrochloric acid and the aqueous layer made basic with ammonia. It is extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is taken up in the minimum amount of isopropanol and the solution slightly acidified with isopropanolic hydrogen bromide to yield the 1 1-(2- dimethylaminoethyl )-9, l O-etheno-anthracene hydrobromide melting at 245246. It is taken up in water, the solution made basic with ammonia, extracted with diethyl ether, the extract dried and evaporated to yield the corresponding free base.

EXAMPLE 4 Preparation of 10,000 tablets each containing 10.0 mg of the active ingredient:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. Thegranulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.

EXAMPLE 5 To the boiling mixture of 17 g lithium aluminum hydride and 100 ml diethyl ether, the solution of 68.5 g l-methylcarbamoyl-dibenzosemibullvalene in 1 liter tetrahydrofuran is added dropwise while stirring and refluxing is continued for 6% hours. After cooling 17 ml water are added dropwise, followed by 34 ml 12 percent aqueous sodium hydroxide and 51 ml water. The mixture is filtered, the filtrate evaporated in vacuo, the residue taken up in the minimum amount of ethanol and the solution acidified with ethanolic hydrochloric acid. The precipitate formed is filtered off and recrystallized from ethanol, to yield the 1- methylaminomethyl-dibenzosemibullvalene hydrochloride of the formula melting at 264-265 with decomposition.

The starting material is prepared as follows: The mixture of 75 g l-carboxy-dibenzosemibullvalene and 500 ml thionyl chloride is allowed to stand overnight at room temperature and evaporated in vacuo. The residue is taken up in 100 ml benzene and the mixture again evaporated in vacuo. The 7 residual dibenzosemibullvalenel-carboxylic acid chloride is taken up in 2 liters ethyl acetate and 365 ml 4 N me- -thylamine in ethyl acetate are added dropwise while EXAMPLE 6 To the stirred suspension of 0.25 g lithium aluminum hydride in 15 ml diethyl ether, the saturated solution of l g 1-pyrrolidinocarbonyl-dibenzosemibullvalene in tetrahydrofuran is added dropwise and the mixture refluxed for 8 hours. After cooling 0.25 ml water, 0.5 ml 12 percent aqueous sodium hydroxide and 0.75 ml water are added while stirring, the mixture filtered and the filtrate evaporated in vacuo. The residue is taken up in diethyl ether, the mixture extracted with 5 percent hydrochloric acid, the extract made basic with ammonia and extracted with diethyl ether. The extract is evaporated and the residue recrystallized from ethanol, to yield the l-pyrrolidinomethyldibenzosemibullvalene of the formula melting at lll115. The corresponding hydrobromide melts at 224227 after recrystallization from isopropanol.

The starting material is prepared as follows: To the solution of 1.25 g dibenzosemibullvalene-l-carboxylic acid chloride in 25 ml ethyl acetate, that of 1.7 g pyrrolidine in 25 ml ethyl acetate is added dropwise and the mixture stirred at room temperature for 2 re hours. It is washed with water, 5 percent hydrochloric acid and water, evaporated and the residue recrystallized from ethanol, to yield the 1-pyrrolidinocarbonyl-dibenzo-semibullvalene melting at 166l69.

EXAMPLE 7 To the suspension of 0.38 g lithium aluminum hydride in 15 ml diethyl ether, the solution of 1.2 g l-(4- methylpiperazino-carbonyl)-dibenzosemibullvalene in ml tetrahydrofuran and 50 ml diethyl ether is added while stirring and the mixture refluxed for 8 hours. After cooling 0.38 ml water, 0.76 ml 12 percent aqueous sodium hydroxide and 1.14 ml water are added, the mixture filtered and the filtrate evaporated in vacuo. The residue is taken up in diethyl ether, the solution extracted with 5 percent hydrochloric acid, the extract made basic with ammonia and extracted with diethyl ether. The extract is evaporated in vacuo, the residue taken up in ethanol, the solution neutralized with ethanolic hydrochloric acid, the precipitate formed filtered off and recrystallized from ethanol, to yield the l-(4- methylpiperazinomethyl)-dibenzosemi-bullvalene hy- QEQglllQTidC of the formula previous precipitate and the whole recrystallized from ethanol, to yield the l-(4-methylpiperazinocarbonyl)- dibenzosemibullvalene melting at 203206.

EXAMPLE 8 The solution of 1.24 g 1-[4-(2-hydroxyethyl)- piperazinocarbonyl]-dibenzosemibullvalene in 50 ml tetrahydrofuran is added dropwise to the stirred suspension of 0.3 g lithium aluminum hydride in 10 ml diethyl ether and the mixture refluxed for 8 hours. After cooling 0.3 ml water, 0.6 ml 12 percent aqueous so dium hydroxide and 0.9 ml water are added, the mixture filtered and the filtrate evaporated in vacuo. The residue is taken up in diethyl ether, the solution aciditied with 6N isopropanolic hydrobromic acid, the precipitate formed filtered off and recrystallized from isopropanol-ethanol, to yield the 1-[4-(2-hydroxyethyl)- piperazinomethyl]-dibenzosemibullvalene dihydrobromide of the formula melting at 260-26l (hygroscopic).

The starting material is prepared as follows: To the solution of 1.25 g dibenzosemibullvalene-l-carboxylic acid chloride in 25 ml ethyl acetate, that of 0.75 g 1-(2-hydroxyethyl)-piperazine in 25 ml ethyl acetate is added dropwise and the mixture stirred for 2 5% hours at room temperature. The precipitate formed is filtered off and washed with ethyl acetate, to yield the l-[4-(2- hydroxyethyl)-piperazinocarbonyl]- dibenzosemibullvalene melting at l56-158.

EXAMPLE 9 The solution of 1.4 g 1-dimethylcarbamoylmethyldibenzo-semibullvalene in 50 ml diethyl ether and 20 ml tetrahydrofuran is added dropwise to the mixture of 0.3 g lithium aluminum hydride in 15 ml diethyl ether while stirring and the mixture refluxed for 6 hours. After cooling 0.3 ml water, 0.6 ml 18 percent aqueous sodium hydroxide and 0.9 ml water are added, the mixture filtered and the filtrate extracted with 5 percent hydrochloric acid. The extract is made basic with am-. monia, extracted with diethyl ether, the extract dried, filtered and evaporated in vacuo. The residue is taken up in isopropanol, the solution acidified with isopropanolic hydrobromic acid, diluted with diethyl ether and the precipitate formed filtered off, to yield the l-( 2-dimethylaminoethyl)-dibenzosemibullvalene hydrobromide of the formula melting at 248-250.

The starting material is prepared as follows: The saturated ethereal solution of dibenzosemibullvalene-lcarboxylic acid chloride (prepared from 2.5 g of the acid and 25 ml thionyl chloride) is added to the ethereal diazomethane solution (prepared from 6.65 g percent N-nitrosomethylure a) and the mixture is allowed to stand at room temperature overnight. it is evaporated in vacuo and the residue recrystallized from ethanol, to yield the l-diazomethylcarbonyldibenzosemibullvalene melting at 173-175 with de-' composition.

To the mixture of 1.3 g thereof, 50 ml benzene and 0.9 ml dimethylamine, the saturated and filtered solution of 2.3 g silver benzoate in triethylamine is added dropwise while cooling and the mixture is stirred overnight at room temperature. it is combined with l g charcoal, filtered and the filtrate evaporated in vacuo. The residue is taken up in diethyl ether, the solution washed with aqueous sodium bicarbonate, dried and evaporated in vacuo, to yield the 1- dimethylcarbamoylmethyl-dibenzosemibullvalene, showing in the IR spectrum a strong band at 1640 cm.

EXAMPLE 10 To the suspension of 0.5 g lithium aluminum hydride in 50 ml diethyl ether, the solution of 2 g 1 -dimethylcarbamoyl-10-chloro-dibenzosemibullvalene in 50 ml diethyl ethcr and 50 ml tetrahydrofuran is added dropwise while stirring and the mixture refluxed for 6 hours. After cooling 0.5 ml water, 1 ml 12 percent aqueous sodium hydroxide and 1.5 ml water are added, the mixture filtered and the filtrate extracted with 5 percent hydrochloric acid. The aqueous phase is made basic with ammonia, the mixture extracted with diethyl ether, the extract evaporated and the residue taken up in ethanol. The solution is acidified with ethanolic hydrobromic acid and the precipitate: formed filtered off,

to yield the l-dimethylaminomethyl-IO -chlorodiben-- zqs s bul s w wmidsst the f n l melting at 208-2l 1 with decomposition.

The starting material is prepared as follows: The mixture of 22.5 g 2-chloroanthracene, 10.4 g ethyl propiolate and ml xylene is refluxed for 1 week. After cooling, it is filtered and the filtrate evaporated in .vacuo. The residue is taken up in 410 m1 methanol and ir irradiated for 23 hours with ultra-violet light of the 2,537A region and the mixture evaporated in vacuo. 2.4 g of the residue is taken up in 24 ml thionyl chloride and the mixture allowed to stand at room temperature overnight. It is evaporated in vacuo, the residue taken up in benzene and the mixture again evaporated in vacuo, to yield the l-chloro-dibenzosemibullvalenel carboxylic acid chloride.

To the solution of 2.5 g thereof in 10 ml ethyl acetate, 9 ml of a 0.04 molar solution of dimethylamine in ethyl acetate is added dropwise and the mixture stirred for 2 hours at room temperature. It is washed with water, percent hydrochloric acid and water, dried, filtered and evaporated, to yield the ldimethylc arbamoyll 0-chloro-dibenzosemibullvalene, which is used as such without further purification.

EXAMPLE 11 To the refluxing suspension of 50 g zinc-copper couple in 200 ml ethanol, 5 g

The extract is dried, evaporated, the residue taken up in ethanol, the solution acidified with ethanolic hydrochloric acid, the precipitate formed filtered off and recrystallized from ethanol-diethyl ether, to yield the 1- dimethylaminomethyl-dibenzo-semibullvalene hydrochloride melting at 252254; it is identical with the compound obtained according to Example 1.

The starting material is prepared as follows: The mixture of l 1.7 g 9,l0-dioxo-4b,9,9a,IO-tetrahydroindeno[ l,2-a]-indene, l 1.5 ml 37 percent aqueous formaldehyde, 12 ml 5N ethanolic dimethylamine and 25 ml ethanol is slowly heated and refluxed for 4 hours. It is evaporated, the residue taken up in diethyl ether, the solution extracted with 5 percent aqueous hydrochloric acid and the aqueous layer made basic with ammonia. lt is extracted with diethyl ether, the extract washed with water, dried filtered and evaporated, to yield the 9,10-dioxo-9a -dimethylaminomethyl-4b,9,9a, lO-tetrahydroinden0[ l,2-a]indene.

To the mixture of 10 g thereof and 100 ml ethanol, 1 g sodium borohydride is added portionwise during V2 hour while stirring. After another A hour the mixture is concentrated in vacuo, the concentrate diluted with water and extracted with diethyl ether. The extract is acidified with 6N ethanolic hydrogen chloride and evaporated in vacuo. The residue is combined with 50 ml thionyl chloride and the mixture stirred at room temperature for 1 day. It is evaporated in vacuo, to

yield the 9,l0-dichloro-9a-dimethylaminomethyl- 4b,9,9a, l0-tetrahydro-indeno-[ l ,2-a]indene hydrochloride.

EXAMPLE 12 The solution of 3.7 g l-carbamoylmethyl-dibenzosemi-bullvalene in 100 ml tetrahydrofuran is added dropwise to the stirred suspension of l g lithium aluminum hydride in 10 ml tetrahydrofuran and 10 ml diethyl ether. The mixture is refluxed for 16 hours, cooled and combined with 1 ml water, 2 ml 12 percent aqueous sodium hydroxide and 3 ml water. It is filtered, the filtrate evaporated in vacuo. the residue taken up in the minimum amount of hot ethanol, the solution cooled and acidified with ethanolic hydrogen chloride. The precipitate formed is filtered off and recrystallized from ethanol-diethyl ether, to yield the l'aminomethyl-dibenzosemibullvalene hydrochloride of the f ma melting above 290.

The starting material is prepared analogous to the method described in Example 5; it melts at 204-205.

EXAMPLE 13 To the suspension of 0.6 g lithium aluminum hydride in 25 ml diethyl ether, the solution of 2.3 g l-dimethylcarbamoyl -lO-methyl-dibenzosemibullvalene in 50 ml diethyl ether is added dropwise while stirring, and the mixture is refluxed for 8 hours. After cooling 0.6 ml water, 1.2 ml 12 percent aqueous sodium hydroxide and 1.8 ml water are added, the mixture filtered and the filtrate evaporated in vacuo. The residue is triturated with petroleum ether, to yield the ldimethylaminomethyll O-methyldibenzosemibullvalene of the formula melting at 97.

The starting material is prepared as follows: The mixture of 5 g Z-methylanthracene, 2.6m] ethyl propiolate and 15 ml xylene is refluxed for one week, cooled, filtered, and the filtrate evaporated in vacuo. The residue is taken up in 20 ml methanol and 20 ml 18 percent aqueous hydroxide, the mixture refluxed for 4 hours, cooled and filtered. The filtrate is acifified with concentrated hydrochloric acid, the precipitate formed filtered off and recrystallized from aqueous ethanol, to yield the 2-methyl-9,lO-ethenoanthracene-l lcarboxylic acid, melting at 2l0216.

The solution of lg thereof in 200 ml tetrahydrofuran is irradiated for 23 hours with ultraviolet light of the 2537 A region and evaporated in vacuo. The residue is taken up in 10 ml thionylchloride and the mixture allowed to stand overnight at room temperature. It is evaporated in vacuo, the residue taken up in 5 ml 5 N dimethylamine in ethyl acetate and the mixture stirred for 3 hours at room temperature. It is washed with water, 5 percent hydrochloric acid and water, dried, filtered and evaporated, to yield the l-dimethylcarbamoyl-lO methyl-dibenzosemilbullvalene.

EXAMPLE 14 The solution of 0.5 g dibenzosemibullvalene-l,2-dicarboxylic acid-N-methylimide in 10 ml tetrahydrofuran is added to the stirred and refluxing mixture of N C14. CH,

'melting at 105.

lt is taken up in the minimum amount of n-propanol and the solution acidified with propanolic hydrogen bromide, to yield the corresponding hydrobromide melting at 255.

The starting material is prepared as follows: The solu tion of 20 g 1 1,12-dicarboxy-9,lO-ethenoanthracene in 2 liters acetone is irradiated for 3 days with a 150W medium pressure ultraviolet lamp, during which time the evaporated acetone is condensed on a cold water noose. The mixture is evaporated in vacuo, the residue triturated with about 20 ml acetonitrile, filtered off and recrystallized from aqueous ethanol, to yield the 1,2- dicarboxydibenzosemibullvalene, melting at 250 with decomposition.

To the stirred solution of 5 g thereof in 100 ml acetonitrile, 8 g l-cyclohexyl-3-(2-morpholinoethyl)- carbodiimide metho-p-toluenesulfonate are added and stirring is continued for 24 hours The mixture is filtered, the filtrate evaporated in vacuo and the residue talten up in chloroform. The solution is washed with water, aqueous sodium hydroxide and water, dried and evaporated. The residue is trituratcd with ethyl acetate, filtered off and recrystallized from ethyl acetate, to yield the dibenZosemibullvalene-l.Z-dicarboxylic acid anhydride melting at 185.

To the solution of 2 g thereof in 50 ml acctonitrile, 25 ml of a 4.5 molar solution of methylaminc in ethyl acetate are added while stirring at room temperature. After 24 hours, the precipitate formed is filtered off, taken up in water, the solution acidified with hydrochloric acid and the precipitate formed filtered off, to yield the dibenzosemibullvalene-l,2-dicarboxylic acid mono-N-methylamide.

The mixture of l g thereof, 20 ml pyridine and 2 g 1- cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p-toluene-sulfonate is stirred for 3 days at room temperature and evaporated in vacuo. The residue is taken up in chloroform, thhe mixture washed with 5 percent aqueous hydrochloric acid, sodium hydroxide and water, dried and evaporated in vacuo, to yield the dibenzosemibullvalene-l ,2-dicarboxylic acid-N- methylimide, melting at 170.

EXAMPLE The solution of l .69 g Z-carboxydibenzoscmibullvalene-l-carboxylic acid dimethylamidc in 150 ml tetrahydrofuran is added dropwise to the suspension of 0.96 g lithium aluminum hydride in 25 ml tetrahydrofuran while stirring and the mixture is refluxed for 8 hours. After cooling, 0.9 ml water, 1.8 ml

18 percent aqueous sodium hydroxide and 2.7 ml water are-added, the mixture filtered and the filtrate evaporated. The residue is taken up in diethyl ether, the solution extracted with 5 percent hydrochloric acid, the aqueous solution made basic with ammonia and extracted with diethyl ether. The extract is dried, filtered, evaporated and the residue recrystallized from ethanol, to yield the 1-dimethylaminomethyl-2-hydroxymethyldibenzosemibullvalene of the formula melting at -147. One gram thereof is taken up in the minimum amount of acetone and the solution neutralized with cyclohexylsulfamic acid, to yield the corresponding cyclohexylsufamate melting at -161.

The starting material is prepared as follows: The mixture of 5 g dibenzosemibullvallene-l,Z-dicarboxylic acid anhydride, 25 ml acetonitrile and 15 ml 5N dimethylamine in ethyl acetate is stirred overnight at room temperature and evaporated in vacuo. The resi due is taken up in 100 m1 N aqueous sodium hydroxide, the mixture filtered, the filtrate acidified with hydrochloric acid, the precipitate formed filtered off and washed with water, to yield the about 10:1 mixture of the 2 isomeric dibenzosemibullvalene-1,2-dicarboxylic acid mono-dimethylamides, melting at 260. 2 g thereof are dissolved in the minimum amount of hot ethanol and the solution allowed to cool to room temperature slowly. The precipitate formed is filtered off, to yield the 2-carboxy-dibenzosemibullvalene l -carboxylic acid dimethylamidc melting at 254 with decomposition.

EXAMPLE l6 To the solution of 2.1 g l-dimethylaminomethyldibenzosemibullvalene in 20 ml methylene chloride, 2.76 g 90 percent 3-chloroperbenzoic acid are added dropwise while stirring and keeping the temperature below 25. The mixture is stirred at room temperature overnight and finally 0.3 g 3-chlloro-perbenzoic acid are added. After 3 hours, the mixture is washed with saturated aqueous sodium bicarbonate and water, dried, filtered and evaporated. The residue is taken up in the minimum amount of isopropanol, the solution acidified with isopropanolic hydrogen bromide and the precipitate formed filtered off, to yield the 1- dimethylaminomethyl-dibenzosemibullvalene-N-oxide hydrobromide of the formula H N(CHa)rHBr 0 0 melting at l82l85.

19 EXAMPLE 17 rahydrofuran and the mixture is refluxed for 8 hours.

After cooling 2.7 ml water, 5.4 ml 12 percent aqueous sodium hydroxide and 8 ml water are added, the precipitate formed filtered off and the filtrate evaporated in vacuo. The residue is taken up in diethyl ether, the solution extracted with percent hydrochloric acid, the aqueous layer made basic with ammonia and extracted with diethyl ether. The extract is dried, evaporated, the residue taken up in ethanol, the solution acidified with ethanolic hydrogen chloride and the precipitate formed filtered off, to yield the lpiperidinomethyl-dibenzosemibullvalene hydrochlojds Qf hFfQEIPRLE. V.

melting at 266-268.

EXAMPLE 18 The solution of 3.4 g l-cyclopropylmethylcarbamoyldibenzosemibullvalene (m.p. l76-l80) in v100 ml tetrahydrofuran is added dropwise to the stirred suspension of 0.9 g lithium aluminum hydride in 50 ml diethyl ether and the mixture refluxed for 8 hours. It is worked up as described in the previous examples,.to yield the l-cyclopropylmethylaminomethyldibenzosemibullvalene hydrochloride of the formula cH1NH-CHg melting at 247-250.

EXAMPLE 19 The solution of 3.9 g l-piperazinocarbonyldibenzosemibullvalene is added dropwise to 1.3 g lithium aluminum hydride in 30 ml tetrahydrofuran while ter, dried, filtered and evaporated. The residue is again taken up in isopropanol and acidified with isporopanolic hydrogen bromide, to yield the lpiperazinomethyl-dibenzosemibullvalene hydrobro- "114 0f. t e formula -HBr melting at 239242.

EXAMPLE 20 The solution of l g l-( l-hydroxyiminoethyl)- dibenzosemibullvalene in 10 ml tetrahydrofuran is added dropwise to the suspension of 0.25 g lithium aluminum hydride and 10 ml diethyl ether while stirring, and the mixture is refluxed for 6 hours. After cooling 0.25 ml water, 0.5 ml 12 percent aqueous sodium hydroxide and 0.75 ml water are added, the precipitate filtered off, the filtrate evaporated and the residue taken up in diethyl ether. The solution is extracted with 5 percent hydrochloric acid, the aqueous solution made basic with ammonia and extracted with diethyl ether. The extract is washed with water, dried, evaporated, the residue taken up in isopropanol and the solution acidified with isopropanolic hydrogen chloride, to yield the l-(l-aminoethyl)-dibenzosemibullvalene hydrochloride of the formula melting at 280282.

The starting material is prepared as follows: The solution of 23.4 g methyl iodide in 40 ml diethyl ether is added dropwise to the suspension of 2.3 g lithium wire in ml diethyl ether while stirring under nitrogen. After the consumption of the lithium, the solution of 10 g l-carboxy-dibenzosemibullvalene in 100 ml diethyl ether is added dropwise while'stirring and the mixture refluxed for 3 hours. After cooling, it is filtered, the filtrate diluted with diethyl ether, washed with ice water, 10 percent aqueous sodium bicarbonate, dried, evaporated and the residue recrystallized from ethanol, to yield the l-acetyl-dibenzosemibullvalene, melting at 204205.

The mixture of 1.7 g thereof, 1.7 g hydroxylamine hydrochloride and 42 ml pyridine is refluxed for 4 hours and evaporated in vacuo. The residue is taken up in water, the mixture extracted with diethyl ether, the extract washed with water, dried, evaporated and the residue recyrstallized from ethanol, to yield the l(lhydroxyiminoethyl)-dibenzosemibullvalene, melting at l 7 1-l 73.

EXAMPLE 21 is washed withwater, evaporated, the residue taken up in ethanol the solution acidified with ethanolic hydrogen chloride and the precipitate recrystallized from ethanol-diethyl ether, to yield the 1-(1- dimethylaminoethyl)-dibenzosemibullvalene hydrochloride of the formula -HCl melting at 248250 with decomposition.

EXAMPLE 22 The solution of 2.2 g 1-dimethylcarbamoyl-2-phenyldibenzosemibullvalene in 35 ml tetrahydrofuran is added to the mixture of 12 ml N-diborane in tetrahydrofuran and 20 ml tetrahydrofuran while stirring. The mixture is refluxed for 6 hours, cooled and 20.6 ml 2N hydrochloric acid are added dropwise. The mixture is concentrated, the aqueous concentrate washed with diethyl ether, made basic with ammonia and extracted with diethyl ether. The extract is washed with water, dried and evaporated, to yield the l-dimethylaminomethyl-Z-phenyl-dibenzosemibullvalene of the formula showing in the NMR spectrum singlets at 278, 215 and 136 cps (60 megacycles in deuterochloroform).

The starting material is prepared as follows: The solution of 10 g 1 l-carboxy-l2-phenyl-9,10- ethenoanthracene in 1.8 liter acetone is irradiated with a medium pressure UV. lamp for 96 hours while siphoned through a glass filter. The filtrate is evaporated in vacuo, the residue triturated with dimethylsulfoxid filtered off and recrystallized from ethyl acetate, to yield the 1-carboxy-2-phenyl-dibenzosemibullvalene melting at 1302 The mixture of 2.2 g thereof and 20 ml thionyl chloride is allowed to stand at room temperature overnight and evaporated in vacuo. The residue is taken up in 20 ml ethyl acetate and 7 ml N dimethylamine in ethyl acetate are added dropwise while stirring at room temperature. After 3 hours, the mixture is washed with water, dried, evaporated and the residue recrystallized from methanol, to yield the l-dimethylcarbamoyl-Z- phenyl-dibenzosemibullvalene melting at 145150.

EXAMPLE 23 Preparation of 10,000 capsules each containing 50.0 mg of the active ingredient:

Formula:

l-Methylaminomethyldibenzosemibullvalene hydrochloride 500.0 g Lactose 2,350.0 g Talcum powder 150.0 g

Procedure:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 2 capsules are filled with 300 mg of the mixture, using a capsule filling machine.

EXAMPLEWZQW H Preparation of 10,000 tablets each containing 25 mg of the active ingredient:

Formula:

1-Methylaminomethyldibenzosemibullvalene hydrochloride 250.0 g Lactose 2,990.0 g Confectioners sugar 30.0 g Corn starch 480.0 g Methylcellulose 80.0 g Colloidal silica 80.0 g Magnesium stearate 40.0 g Purified water q.s..

Procedure:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, the sugars, methylcellulose, silica, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 30 ml water and the suspension added to 400 m1 boiling water. The

MPLE The solution of 3.1 g l-(Z-dimethylcarbamoylethyl)- dibenzosemibullvalene in ml diethyl ether is added dropwise to the suspension of 0.8 g lithium aluminum hydride in 15 ml diethyl ether while stirring, and the mixture is refluxed for 5 hours. After cooling, 0.8 ml water, 1.6 ml 12 percent aqueous sodium hydroxide and 2.4 ml water are added respectively. The inorganic salts are filtered off and the filtrate extracted with 5 percent aqueous hydrochloric acid. The extract is made basic with ammonia and the mixture extracted with diethyl ether. The extract is washed with water, dried and evaporated. The residue is taken up in the 'minimum amount of anhydrous ethanol, the solution acidified with ethanolic hydrochloric acid and the precipitate formed is filtered and recrystallized from isopropanol-diethyl ether, to afford the 1-(3- hydromelting at 217218.

The starting material is prepared as follows: The solution of 15 g 1-carboxy-dibenzosemibullvalene in 150 ml tetrahydrofuran is added dropwise to the suspension of 4.8 g lithium aluminum hydride in 50 ml diethyl ether while stirring, and the mixture is refluxed for 5 hours. After cooling, 4.8 ml water, 9.6 ml 12 percent aqueous sodium hydroxide and 14.4 ml water are added consecutively. The salts are filtered off and the filtrate evaporated, to yield the lhydroxymethyldibenzosemibullvalene melting at 140l42.

The solution of 2.8 g thereof in 15 ml pyridine is added in one portion to the ice-cooled suspension of 3.6 g chromium trioxide and 45 ml pyridine. The mixture is allowed to stir and warm up to room temperature overnight. It is diluted with methylene chloride and the solids are filtered off. The filtrate is washed consecutively with 1N aqueous hydrochloric acid, 5 percent evaporated. The solids formed are recrystallized from benzene-petroleum ether, to yield the 1- formyl-dlbenzosemibullvalene, melting at l63-165.

To the suspension of 0.34 g 57 percent sodium hydridc in mineral oil and 8 ml 1,2-dimethoxyethane, 1.5 ml triethyl phosphonoacetate are added dropwise while stirring at 20. The mixture is stirred 1% hours at room temperature and the solution of 1.3 g l-formyldibenzosemibullvalene in 25 ml dimethoxyethane is added dropwise. The resulting mixture is stirred at room temperature 2 /2 hours, poured into water and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from ethanolpetroleum ether, to yield the 1-(2-carbethoxyethenyl)- dibenzosemibullvalene melting at 9798.

The mixture of 1 g thereof, 0.5 g percent palladium-on-carbon and 50 ml ethanol is hydrogenated at about 3 atm for 1 hour at room temperature. The catalyst is filtered off and the filtrate evaporated underreduced pressure, to afford the l-(2-carbethoxyethyl)- dibenzosemibullvalene.

The mixture of 3 g thereof, 10 ml 18 percent aqueous sodium hydroxide and 4 ml methanol is reflxued for 3 hours, cooled, diluted with water and acidified with percent aqueous hydrochloric acid. The mixture is extracted with diethyl ether, the extract washed, dried and evaporated. The residue is treated with 15 ml thionyl chloride and the mixture allowed to stand at room temperature overnight. It is evaporated under reduced pressure and the residue stirred overnight at room temperature with the mixture of 10 ml 25 percent aqueous dimethylamine and 10 ml acetone. The mixture is evaporated, the residue taken up in Water and extracted with diethyl ether. The extract is washed with water,

dried and evaporated, to yield the 1-(2- dimethylcarbamoylethyl)-dibenzosemibullvalene.

EXAMPLE 26 The mixture of 1 g of 1-(3-dimethylaminoprop-2- enyl)-dibenzosemibullvalene hydrobromide, 50 ml of water and 0.2 g of 10 percent palladium on charcoal is hydrogenated at room temperature and at atmospheric pressure until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate made basic with ammonia and extracted with diethyl ether. The extract is dried, evaporated and the residue taken up in 6N ethanolic hydrogen chloride. The mixture is concentrated and the precipitate formed recrystallized from isopropanol-diethyl ether, to yield the l-(3- dimethylaminopropyl)-dibenzosemibullvalene hydrochloride melting at 217 to 218; it is identical with that obtained according to Example 25.

The starting material is prepared as follows: The mixture of 6 of 1-(2-carboethoxyethenyl)- dibenzosemibullvalene, 20 ml of 18 percent aqueous sodium hydroxide and 8 ml of methanol is refluxed for 3 hours, cooled and acidified with 15 percent hydrochloric acid. The mixture is extracted with diethyl ether, the extract washed with water, dried, evaporated and the residue recrystallized from isopropanol, to yield the 1-( 2-carboxyethenyl)-dibenzosemibullvalene, melting at 200-202.

The mixture of 4.2 g thereof and 22 ml of thienyl chloride is allowed to stand at room temperature overnight and evaporated under reduced pressure. The residue is taken up in 20 ml of benzene and the mixture again evaporated, to yield the corresponding acid chloride.

The mixture of 4 g thereof, 10 ml of acetone and 10 ml of 25 percent aqueous dlmethylamine is stirred at room temperature for 2 days and slowly evaporated. The residue is taken up in water, the mixture extracted with ethyl acetate, the extract washed with water, dried and evaporated, to yield the l-(2-dimethylcarbamoylethenyl)-dibenzosemibullvalene.

The solution of 3.1 g thereof in ml of tetrahydrofuran is added dropwise to the stirred suspension of 0.8 g of lithium aluminum hydride in 25 ml of diethyl ether at the rate sufficient to maintain reflux. The mixture is refluxed for 7 more hours, allowed to stand at room temperature overnight and combined with 0.8 ml water, 1.6 ml 12 percent aqueous sodium hydroxide at 2.4 ml of water in this order. The mixture is filtered, the filtrate evaporated and the residue taken up in water. The mixture is extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in isopropanol and the solution acidified with isopropanolic hydrogen bromide, to yield the l- (3-dimethylaminoprop-2-enyl)-dibenzosemibullvalene hydrobromide melting at 181 to 183.

EXAMPLE 27 The mixture of 1.0 g l-dimethylaminomethyldibenzosemivullvalene, 1.0 ml dimethyl sulfate and 30 ml acetone is refluxed for 3 hours, cooled and filtered. The residue is recrystallized from ethanol-ethyl acetate, to yield the 1-trimethylammoniummethyldibenzosemibullvalene methosulfate of the formula showing I. R. bands at 740, 760, 1 and 1224 cm.

R: alk-Am in which each of Ph, and Ph is unsubstituted 1,2- phenylene of l,2-phenylene substituted by one member selected from the group consisting of lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylmercapto, halogeno, trifluoromethyl, nitro, amino, di-lower alkylamino, lower alkanoyl and lower alkylsulfonyl, alk is lower alkylene, Am is amino, mono or di-lower alkylamino, 3 to 7 ring-membered cycloalkylamino, N- lower alkylN-cycloalkylamino, cycloalkyl-lower alkylamino or N-lower alkyl-N-cycloalkyl-lower alkylamino, R is hydrogen, aliphatic, araliphatic or aromatic radical or lower alkylene lower alkyl, hydroxy-lower alkyl, unsubstituted phenyl or phenyl substituted as described for Ph and each of R and R is hydrogen or lower alkyl, the N-oxide or a therapeutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1, in which formula each of P11 and Ph is R.,-1,2-phenylene, alk is lower alkylene, Am is amino, mono-r di-lower alkylamino, 3 to 7 ring-membered cycloalkylamino or cycloalkyl-lower alkylamino R is hydrogen, lower alkyl, hydroxy-lower alkyl or R -phenyl, each of R and R is hydrogen or lower alkyl and R is hydrogen, lower alkyl, lower alkoxy, halogeno, trifluoromethyl, nitro, amino or di-lower alkylamino, or the N-oxide, or a therapeutically acceptable acid addition salt thereof.

3. A compound as claimed in claim 2 and having the formula R C EM-Am;

in which Am, is amino, monoor di-lower alkylamino or 3 to 5 ring-membered cycloalkylmethylamino, R is hydrogen, methyl, hydroxymethyl or phenyl, each of R and R,- is hydrogen or methyl, each of R and R is hydrogen, methyl, methoxy, chloro or nitro and n is the integer l, 2 or 3, the N-oxide or a therapeutically acceptable acid addition salt thereof.

4. A compound as claimed in claim 3, in which formula Am, is amino, methylamino, ethylamino, dimethylamino, diethylamino or cyclopropylmethylamino, R is hydrogen, hydroxymethyl or phenyl, each of R and R is hydrogen, each of R and R is hydrogen, methyl or chloro and n is the integer l, 2 or 3, the N-oxide or a therapeutically acceptable acid addition salt thereof.

5. A compound as claimed in claim 2 and having the formula (CH -A In 2 in which Am is amino, methylamino, ethylamino, dimethylamino, di-ethylamino or cyclopropylmethylamino, R is hydrogen, methyl or chloro and n is the integer l, 2 or 3, the N-oxide or a therapeutically acceptable acid addition salt thereof.

6. A compound as claimed in claim 5 and being the l-methylaminomethyl-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.

7. A compound as claimed in claim 5 and being the l-dimethylaminomethyl-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.

8. A compound as claimed in claim 5 and being the 1-(2'dimethy1aminoethyl)-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.

9. A compound as claimed in claim 5 and being the l-( 3-dimethylaminopropyl )dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof. =l is TUNI ED STATES PATENT 0mm; CERTIFICATE OF CORRECTION Patent No. 3,818,020 bated J 97 I Ifive t r( HARLES FERDINAND HUEBNER It is certified that error appears in the ab0ve-identified patent and that said Letters Patent are hereby corrected'as shown below:

Page 1, after [54]" the title should read I-AMINOALKYL-DIBENZOSEMI- BULLVALENES AND THE SALTS THEREOF v Column '25, I line 12, after "phenylene" delete "of" and I I insert or line 21, after "hydrogem insert an Signed and sealed this 5th day of November 1974.

(SEAL) Attest:

McCOY M. GIBSON JR, C. MARSHALL DANN Attesting Officer Commissioner of Patents 3 13 UMTE s'mms PATENT owmi. V

@E'mm'm m mz'amm Patent No. 318181020 bated J 18, 97

HARLES FERDINAND HUEBNER 'It is certified that error appears in the above-idenfified patent and that said Letters Patent are hereby corrected as. shown below:

Page 1, after "[54]" the title should read l-AMINOALKYL-DIBENZOSEMI- BULLVALENES AND THE SALTS I THEREOF Column 25, line 12, after "phenylene" delete "of" and insert or -5 line 21, after "hydrogen," insert an Signed and sealed this 5th day of November 1974.

(SEAL) Attest:

MCCOY Mn GIBSON JR C. MARSHALL DANN Ava-testing Officer Commissioner of Patents 

2. A compound as claimed in claim 1, in which formula each of Ph1 and Ph2 is R4-1,2-phenylene, alk is lower alkylene, Am is amino, mono-or di-lower alkylamino, 3 to 7 ring-membered cycloalkylamino or cycloalkyl-lower alkylamino R is hydrogen, lower alkyl, hydroxy-lower alkyl or R4-phenyl, each of R1 and R2 is hydrogen or lower alkyl and R4 is hydrogen, lower alkyl, lower alkoxy, halogeno, trifluoromethyl, nitro, amino or di-lower alkylamino, or the N-oxide, or a therapeutically acceptable acid addition salt thereof.
 3. A compound as claimed in claim 2 and having the formula
 4. A compound as claimed in claim 3, in which formula Am1 is amino, methylamino, ethylamino, dimethylamino, diethylamino or cyclopropylmethylamino, R5 is hydrogen, hydroxymethyl or phenyl, each of R6 and R7 is hydrogen, each of R8 and R9 is hydrogen, methyl or chloro and n is the integer 1, 2 or 3, the N-oxide or a therapeutically acceptable acid addition salt thereof.
 5. A compound as claimed in claim 2 and having the formula
 6. A compound as claimed in claim 5 and being the 1-methylaminomethyl-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.
 7. A compound as claimed in claim 5 and being the 1-dimethylaminomethyl-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.
 8. A compound as claimed in claim 5 and being the 1-(2-dimethylaminoethyl)-dibenzosemibullvalene or a therapeutically acceptable acid addition salt thereof.
 9. A compound as claimed in claim 5 and being the 1-(3-dimethylaminopropyl)-dibenzosemibullvalene or a therapeutically acceptable acid additioN salt thereof. 